Available Technology
Increasing neural regeneration following traumatic injury: Modulation of neuronal outgrowth with HSPG (heparin) and CSPG (chondroitin)
Technology:
Novel therapeutic approach to increase neural regeneration and an injury biomarker to localize the site of the neural injury
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Research in the Flanagan laboratory provides new therapeutic approaches to enhance neural regeneration, and sheds new light on the functions of the RPTP family. Therapeutic applications include spinal cord injury, as well as other forms of neural injury and neurodegeneration that involve reactive astrogliosis such as stroke, traumatic brain injury, peripheral nerve injury, skin burn and eye injury affecting optic nerve fibers. Specifically, this technology covers novel therapeutic approaches to induce axonal outgrowth of a neuron, including agents which:
• Inhibit interaction between RPTPsigma and CSPGs: Develop a therapeutic agent to enhance neural regeneration by inhibiting the interaction between CSPGs and RPTPsigma. The identification of the specific binding site on RPTPsigma that interacts with CSPGs provides a lead for drug design.
• Induce clustering of RPTPsigma with HSPGs and heparin oligosaccharides: Develop a therapeutic agent to enhance neuronal outgrowth by inducing the clustering of RPTPsigma. Agents that promote clustering of RPTPsigma include HSPGs and heparin oligosaccharides.
In addition, the lab discovered that RPTPsigma can be used as a novel injury biomarker. RPTPsigma was shown to selectively recognize injured versus uninjured adult CNS tissue. Therefore, administration of a tagged form of RPTPsigma can be used to anatomically localize the site of neural injury.
Innovations and Advantages
Researchers in the Flanagan lab uncovered a novel therapeutic approach to increase neural regeneration following traumatic injury such as spinal cord injury.
Type II receptor protein tyrosine phosphatases (RPTPs) are cell surface receptors important for the development, function and repair of the nervous system. They localize to axonal growth cones where they promote outgrowth, mediate axon guidance and participate in excitatory synapse formation and maintenance.
The Flanagan lab discovered that one member of the RPTP family, RPTPsigma, binds both chondroitin sulphate proteoglycans (CPSGs) and heparin sulphate proteoglycans (HSPGs), which are known to play important roles in neuronal guidance and connectivity. The lab further demonstrated that these proteoglycans mediate opposing effects on neuronal outgrowth, with CSPGs inhibiting and HSPGs promoting axon growth, and uncovered the molecular mechanisms of these interactions.
CSPGs inhibit neuronal outgrowth: The injured adult central nervous system inhibits axon outgrowth, thereby limiting recovery from traumatic injury. Following neural injury, CSPG is dramatically upregulated within the extracellular matrix of scar tissue, resulting in inhibition of nerve regeneration.
The Flanagan lab discovered the first identified receptor for a CSPG, RPTPsigma (Shen et al. Science 2009; 326:592-6). The lab demonstrated that CSPG3, a major CSPG produced by reactive astroglia following spinal cord injury, binds to RPTPsigma. The lab further identified the binding site for this interaction and demonstrated that RPTPsigma is functionally involved in the inhibitory effects of CSPG on neural regeneration.
HSPGs promote neuronal outgrowth: In contrast to CSPGs, HSPGs strongly promoted outgrowth of wild type neurons. This effect was completely abolished in RPTPsigma deficient neurons.
To understand the observed dichotomy in CSPG/HSPG function mediated through a common receptor, the lab generated a series of deletion constructs of the type II RPTPs. Their research showed that heparin sulphate (HS) induced clustering of RPTPsigma, while chondroitin sulphate (CS) did not induce clustering of any of the type II RPTPs. These contrasting effects were mediated by differences in chemical structure between HS and CS. Using a competitive binding assay, the lab further showed that excess CS could inhibit HS-induced clustering.
Molecular switch: Findings from their research suggest that HS-stabilized RPTPsigma clusters are growth promoting. In contrast, at the scar tissue, the abundantly secreted CS molecules likely out-compete the HS interactions, disrupting the clusters to establish a more even distribution of RPTPsigma across the cell surface. This breakdown of microdomain structure could serve as a molecular switch to trigger the collapse of neuronal growth cones.
Additional Information
Intellectual Property Status: Patent(s) pending
This technology, which is currently available for worldwide, exclusive licensing.
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Inventor(s):
Flanagan, John G.
Shen, Yingjie
Silver, Jerry
Tenney, Alan Peter
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For further information, please contact:
Grant Zimmermann, Director of Business Development
(617) 495-3067
Reference Harvard Case #3588